This program began 14 years ago to explore the renal and vascular mechanisms involved in the long-term control of arterial pressure. Based on a number of important new observations, we have currently focused our studies on three important interactive controllers of renal and peripheral vascular tone and arterial pressure, i.e. nitric oxide (NO), 20- hydroxyeicotetraenoic acid (HETE) and angiotensin II (ANGII). Project 1 examines the hypothesis that stimulation of NO production in the renal medulla is critical for the maintenance of blood flow to this region and for maintenance of normal levels of arterial pressure in response to elevations in intrarenal ANGII or norepinephrine. Project 2 examines the influence of sodium intake on the expression of nitric oxide synthase (NOS) isoforms in the renal medulla and the role that each of these isoforms plays in the regulation of renal tubular and vascular function in the portion of the kidney. Project 3 examines a new NO signal transduction pathway whereby inhibition of 20-HETE production in the renal vasculature mediates the activation of K/+ channels and the vasodilation responses to NO. Project 4 tests the hypothesis that the P4504A2 enzymes serves as an "oxygen sensor" whereby increases in tissue PO/2 stimulate the local production of 20-HETE leading to arterial constriction and autoregulation of blood flow. Project 5 explores the hypothesis that reduction of ANGII during periods of high salt intake mediates rare-faction of skeletal muscle microvessels. Based of evidence that ANGII alters expression of both NO and 20-HETE taken together, these five projects provide an important link between sodium homeostasis, the regulation of renal and peripheral vascular tone, and the long-term control of arterial pressure. This Program builds upon unique interdisciplinary and collaborative strengths and each project takes advantage of current molecular biochemical technologies in conjunction with state of the art integrative studies at the organ level and long-term studies in conscious animals. Successful completion of this work should enhance understanding of the biochemical and molecular basis of these mechanisms in the control of sodium and water excretion, renal and peripheral vascular function, and the long-term control of arterial pressure.